NADPH Oxidase4is A Potential Target For The Intervention Of Cancer Metastasis

NADPH oxidase4(NOX4) is a multi-transmembrane protein that interact with p22subunit to form a heterodimer enzyme complex. It catalyzes the transfer of electrons from NADPH to oxygen molecule to generate superoxide (·02-) that mostly is the original source of reactive oxygen species (ROS). Activity of this enzyme mainly depends on the expression level of NOX4, according to various reports. Several lines of evidence suggest that TGF-β induces ROS production which then regulates the signaling pathways as well as biological functioning of TGF-β, through NADPH oxidase including NOX1, NOX3, and NOX4. However, the role of NOX in the functioning of TGF-p on cancer cells is hardly known. Here we show (1) that TGF-β induces ROS production in breast cancer4T1cells and enhances cell migration and that the effect of TGF-β depends on NOX4expression,(2) that knockdown of NOX4via RNAi significantly decreases the migration ability of4T1cells in the presence or absence of TGF-β and significantly attenuates distant metastasis of4T1cells to lung and bone,(3) that Schisandrin B (Sch B), a naturally-occurring dibenzocyclooctadiene lignan with very low toxicity, is a novel NOX inhibitor and its IC50toward NOX4is9.3μM, and (4) that Sch B suppresses TGF-P-induced and NOX4-associated ROS production and morphological transformation in4T1cells and inhibits TGF-P-enhanced cell migration. Similar to NOX4knockdown observed in this study, Sch B can inhibit TGF-p induced EMT and significantly attenuated4T1cells’ distant metastasis to lung and bone without significant effect on the tumor growth in our recently-published study. In line with previous reports, the study suggests that pharmacologically targeting NOX4may be a potential approach to disrupt cancer metastasis.